The proposed R21 application will investigate the potential of mesenchymal stem/stromal cells (MSC) in enhancing mucosal tissue repair/renewal and immune recovery in HIV-induced chronic inflammatory disease. MSCs secrete immunomodulatory, anti-inflammatory, anti-apoptotic, trophic and angiogenic factors that dampen inflammation and enhance tissue repair and are being actively investigated in several clinical trials. However, the potential of MSCs in tissue renewal during chronic inflammatory diseases of infectious etiology has not been fully explored. HIV disease progression is driven by progressive CD4+ T cell loss and unresolved chronic immune activation. Early pathogenic changes in the gut mucosa in HIV infection may be important in the persistence inflammation and viral reservoirs. Antiretroviral treatment markedly suppresses viral replication but is unable to completely resolve chronic immune activation or eradicate viral reservoirs. An imbalance of inflammatory/anti-inflammatory networks, resulting in inflamed mucosa, may be an important contributor to the persistent immune activation. We propose to utilize simian immunodeficiency virus (SIV) infected non-human primate model of AIDS to investigate potential therapeutic benefits of MSCs and possible mechanisms of action in tissue repair and immune recovery. SIV-infected rhesus macaques are well suited for investigating the therapeutic benefit of MSC transplantation and to elucidate mechanisms of MSC biologic action within the inflamed gut microenvironment. We will test the hypothesis that systemic MSC administration will minimize cell injury and death at mucosal sites in the SIV infected rhesus macaques and facilitate immune recovery. This proposal leverages on our unique strengths in stem cell biology, SIV-infected rhesus macaque model of AIDS, isolation of purified rhesus macaque MSCs and collective technical expertise in MSC cultures, gut mucosal immunology and immune activation. The overall objective of this R21 proposal is to investigate the effects of MSC administration on the gut mucosal repair/renewal and immune recovery and to determine the mechanisms of action in SIV infected rhesus macaques. The study has two specific aims. Aim 1: To determine the effect of MSC therapy on CD4 T cell loss, viral loads and immune activation/inflammation in peripheral blood compartment of SIV infected macaques. Aim 2: To determine the effect of MSC therapy on gut mucosal injury and repair and elucidate the molecular networks mediating its mechanism of action. Changes in T cell subset distribution and cellular activation markers (multicolor flow cytometry, PCR), inflammatory mediators (ELISA), viral loads (real-time PCR), mucosal injury and inflammation (immunohistopathology) and signaling networks for tissue renewal (western blots and qRT-PCR) will be measured. The data will be analyzed to determine the effects of MSC administration in SIV infected animals compared to those not receiving MSC. The proposed study will provide an innovative approach to resolve HIV associated mucosal tissue damage and chronic immune activation through MSC administration in the primate model and will provide rationale for the development of novel therapeutic strategies. The study may elucidate new mechanisms by which MSCs modulate the immune system and promote gut regeneration in chronic inflammatory infections.